TY - JOUR TI - Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts AU - Parker, Margaret M AU - Hao, Yuan AU - Guo, Feng AU - Pham, Betty AU - Chase, Robert AU - Platig, John AU - Cho, Michael H AU - Hersh, Craig P AU - Thannickal, Victor J AU - Crapo, James AU - Washko, George AU - Randell, Scott H AU - Silverman, Edwin K AU - San José Estépar, Raúl AU - Zhou, Xiaobo AU - Castaldi, Peter J A2 - Morris, Andrew P A2 - McCarthy, Mark I A2 - Morris, Andrew P A2 - Wain, Louise VL - 8 PY - 2019 DA - 2019/07/25 SP - e42720 C1 - eLife 2019;8:e42720 DO - 10.7554/eLife.42720 UR - https://doi.org/10.7554/eLife.42720 AB - Murine studies have linked TGF-β signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb region downstream from TGFB2. Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate TGFB2 expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the TGFB2 promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~ 100 bp region containing rs1690789 resulted in decreased TGFB2 expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-β pathway to emphysema in humans. KW - COPD KW - genome-wide association study KW - transcriptomics KW - TGF-beta signaling KW - emphysema KW - bioinformatics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -